Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic human syndrome of premature aging. Children with this rare condition are normal at birth, but by age 2 they have stopped growing, lost their hair, and shown skin changes and loss of subcutaneous tissue that resemble the ravages of old age. They rarely live past adolescence, dying almost always of advanced cardiovascular disease (heart attack and stroke). The classic syndrome has never been observed to recur in families. Our laboratory discovered that nearly all cases of HGPS harbor a de novo point mutation in codon 608 of the LMNA gene. This mutation causes disease by creating an abnormal splice donor, generating a mRNA with an internal deletion of 150 nt. This is translated into a mutant form of the lamin A protein (referred to now as progerin) that lacks 50 amino acids near the C-terminus. We have shown that progerin acts as a dominant negative to disrupt the structure of the membrane scaffold. Data from our group has also demonstrated that progerin interferes with proper chromosome segregation during mitosis. A mouse model for HGPS has been developed. Animals carrying a human BAC transgene bearing the codon 608 mutation show progressive loss of smooth muscle cells in the media of large vessels, with replacement by proteoglycan. Thus, the mouse model nicely replicates the cardiovascular phenotype of HGPS. We are actively exploring the possibility that farnesyl transferase inhibitors (FTIs) might be beneficial in HGPS, since lamin A is a farnesylated protein. Treatment of progeria fibroblasts growing in cell culture demonstrates that FTIs are capable of reversing the dramatic nuclear blebbing that is the hallmark of the disease. A trial of FTIs in the progeria mouse model has demonstrated that this drug treatment is capable of preventing and even reversing the cardiovascular phenotype. A clinical trial of FTIs in children with the disease has been initiated in May 2007. Homozygotes for the mouse BAC transgenic have also now been bred, and show a considerably more severe phenotype. Those animals are now being used to test the effect of the combination treatment of FTIs, statins, and bisphosphonates. A new line of research involves the use of rapamycin to increase turnover of progeria aggregates in the proteasome, and shows considerable promise. While progerin has a dramatic effect on nuclear structure and mitosis, it also disrupts the connections between the nuclear scaffold and chromatin. The consequences include disregulation of gene expression and epigenetic modification. To explore this in detail, we are studying passage-matched normal and HGPS fibroblasts, using gene expression microarray analysis and chromatin immunoprecipitation coupled with high throughput sequencing (ChIP-seq). We have also shown that progerin is made in small amounts in normal individuals, and appears to increase in quantity as cells approach senescence. Recent data points to an interesting connection between shortening of telomeres and activation of alternative splicing of dozens of genes, including production of progerin from a normal LMNA gene. In this way, senescence may proceed by a positive feedback loop.